Erlotinib



Better Known as: Tarceva

 * Marketed By: Genentech, OSI Pharmaceutials, & Roche
 * Major Indication: Pancreatic & Small Cel Lung Cancer
 * Drug Class: EGFR Inhibitor
 * Date of FDA Approval (Expiration): 2005 (2020)
 * 2009 Sales: $1.2 Billion
 * Importance: It is one of the best selling and most effective treatments for several types of cancer. It is an improved version of Iressa.
 * See Pharmaceutical Drugs for more information about other drugs and disorders

Mechanism of Action
Epidermal Growth Factor Receptors are overexpressed in many types of human carcinomas including lung, pancreatic, and breast cancer, and are often mutated. This overexpression leads to excessive activation of the anti-apoptotic Ras signalling cascade, resulting in uncontrolled DNA synthesis and cell proliferation. Studies have revealed that the EGFR tyrosine kinase domain is responsible for activating this Ras signaling cascade. Upon binding ligands like Epidermal Growth Factor, EGFR dimerizes and autophosphorylates several tyrosine residues at its C-terminal domain. Upon phosphorylation, EGFR undergoes a conformational change, revealing an additional binding site capable of eliciting downstream activation of other signaling proteins. Erlotinib inhibits the EGFR tyrosine kinase by binding to the ATP-binding site located within the kinase domain. EGFR uses residues Asp 831, Lys 721, Thr 766, Leu 820, Gly 772, Phe 771, Leu 694, Pro 770, Met 769, Leu 768, Gln 767 & Ala 719 to tightly bind the inhibitor. Unable to bind ATP, EGFR is incapable of autophosphorylating its C-terminal tyrosines, and the uncontrolled cell-proliferation signal is terminated.